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Introduction: Plasma citrulline is not incorporated in endogenous or exogenous proteins so it is a theoretical marker of villous atrophy. Our aim was to correlate plasma citrulline levels with severity of villous atrophy in celiac patients. Methods: Observational case-control study longitudinal in children 16 month-old to 14 year-old: 48 with untreated celiac disease, 9 celiac children under gluten free diet and 35 non-celiac healthy children. Plasma amino acids concentration is determined, expressed in [mu]mol/L, and so are other clinical and analytical data. Results: No statistically significative difference found in the referring to BMI, age or renal function. Small increase in fecal fat in celiac children. Citrulline, arginine and glutamine are significantly lower in cases (17.7 [mu]mol/l, 38.7 [mu]mol/l, 479.6 [mu]mol/l respectively) than in controls (28.9 [mu]mol/l, 56.2 [mu]mol/l, 563.7 [mu]mol/l). Citrulline levels are significantly lower in the severe degrees of atrophy than in mild ones (13.8 [mu]mol/l vs. 19.7 [mu]mol/l, p < 0.05), not happening so with rest of amminoacids. Summary: Postabsortive mean of plasma citrulline is a good marker of reduction in enterocyte mass in celiac patients with villous atrophy; secondary reduction in plasma arginine too. Just a small histological alteration in intestinal biopsy is enough to differentiate citrulline in cases and controls and besides it can be seen that high levels of atrophy present with lower plasma citrulline. [ABSTRACT FROM AUTHOR]

Background: Hereditary fructose intolerance (HFI) is a rare inborn error of fructose metabolism caused by the deficiency of aldolase B. Since treatment consists of a fructose-, sucrose- and sorbitol-restrictive diet for life, patients are at risk of presenting vitamin deficiencies. Although there is no published data on the status of these vitamins in HFI patients, supplementation with vitamin C and folic acid is common. Therefore, the aim of this study was to assess vitamin C and folate status and supplementation practices in a nationwide cohort of HFI patients., Methods: Vitamin C and folic acid dietary intake, supplementation and circulating levels were assessed in 32 HFI patients and 32 age- and sex-matched healthy controls., Results: Most of the HFI participants presented vitamin C (96.7%) and folate (90%) dietary intake below the recommended population reference intake. Up to 69% received vitamin C and 50% folic acid supplementation. Among HFI patients, 15.6% presented vitamin C and 3.1% folate deficiency. The amount of vitamin C supplementation and plasma levels correlated positively (R = 0.443; p = 0.011). Interestingly, a higher percentage of non-supplemented HFI patients were vitamin C deficient when compared to supplemented HFI patients (30% vs. 9.1%; p = 0.01) and to healthy controls (30% vs. 3.1%; p < 0.001)., Conclusions: Our results provide evidence for the first time supporting vitamin C supplementation in HFI. There is great heterogeneity in vitamin supplementation practices and, despite follow-up at specialised centres, vitamin C deficiency is common. Further research is warranted to establish optimal doses of vitamin C and the need for folic acid supplementation in HFI., (© 2022. The Author(s).)

Hereditary Fructose Intolerance (HFI) is an autosomal recessive inborn error of metabolism characterised by the deficiency of the hepatic enzyme aldolase B. Its treatment consists in adopting a fructose-, sucrose-, and sorbitol (FSS)-restrictive diet for life. Untreated HFI patients present an abnormal transferrin (Tf) glycosylation pattern due to the inhibition of mannose-6-phosphate isomerase by fructose-1-phosphate. Hence, elevated serum carbohydrate-deficient Tf (CDT) may allow the prompt detection of HFI. The CDT values improve when an FSS-restrictive diet is followed; however, previous data on CDT and fructose intake correlation are inconsistent. Therefore, we examined the complete serum sialoTf profile and correlated it with FSS dietary intake and with hepatic parameters in a cohort of paediatric and adult fructosemic patients. To do so, the profiles of serum sialoTf from genetically diagnosed HFI patients on an FSS-restricted diet ( n = 37) and their age-, sex- and body mass index-paired controls ( n = 32) were analysed by capillary zone electrophoresis. We found that in HFI patients, asialoTf correlated with dietary intake of sucrose (R = 0.575, p < 0.001) and FSS (R = 0.475, p = 0.008), and that pentasialoTf+hexasialoTf negatively correlated with dietary intake of fructose (R = -0.386, p = 0.024) and FSS (R = -0.400, p = 0.019). In addition, the tetrasialoTf/disialoTf ratio truthfully differentiated treated HFI patients from healthy controls, with an area under the ROC curve (AUROC) of 0.97, 92% sensitivity, 94% specificity and 93% accuracy.

Incidental findings on newborn screening (NBS) are results that are not the target of screening within a given NBS program, but rather are found as a result of the screening and resulting diagnostic workup for that target. These findings may not have an immediate clinical impact on the newborn, but are sometimes an additional benefit of NBS programs and may be considered secondary targets of NBS programs. This work describes four case reports that had incidental findings on the NBS, which eventually led to the diagnosis of another metabolic disease instead of the one that was initially suspected. The first case was a new defect in the cationic amino acid transporter-2 (CAT-2), which was oriented as an arginase-1 deficiency in the newborn. The second case was a maternal glutaric aciduria type 1 (GA-1) that mimicked a carnitine transporter deficiency in the newborn. The third report was a case of lysinuric protein intolerance (LPI), which appeared as high levels of citrulline on the NBS. The fourth case was a mother with homocystinuria that was diagnosed during the biochemical study of vitamin B 12 status. All cases provide new or interesting data that will help guide differential diagnosis in the future.

Introduction and Objectives: Thiopurines are drugs widely used in patients for the maintenance of remission in inflammatory bowel disease. The optimal plasma levels are known, but there is controversy about whether the need for other drugs is reduced or is cost-effective. The aim of this study is to describe the use of the optimised treatment with thiopurines in paediatric patients with inflammatory bowel disease followed up in this Unit since the introduction of determining the drug levels., Material and Methods: A descriptive retrospective study was conducted in which the plasma values of 6-thioguanine (6-TGN), 6-methyl-mercapto-purine (6-MMP), and their ratios were analysed using liquid chromatography. Other variables were collected, such as clinical status, analytical and demographic variables of patients with inflammatory bowel disease followed up in this Unit., Results: A total of 72 patients were included, and 149 determinations of metabolites were performed. The 6-TGN levels were found to below the therapeutic range in 61.5% of patients (in 7 cases due to lack of adherence to therapy), and 6-MMP was in the toxicity range in 7.4%. After the determination of 77 specimens, some action was taken, such as modifying the dose, change of formula, or withdrawing the drug. Only 9 patients were scaled to a biological drug (13.4% of the total on single therapy). No association was found between the activity of the disease and the thiopurine levels., Conclusions: In our experience, the monitoring of thiopurine levels helped to modify the drug dose that the patient received, adjusting their therapeutic levels, and potentially avoiding the addition of new drugs., (Copyright © 2019. Publicado por Elsevier España, S.L.U.)

Background: In phenylketonuria (PKU), weaning is considered more challenging when compared to feeding healthy infants. The primary aim of weaning is to gradually replace natural protein from breast milk or standard infant formula with solids containing equivalent phenylalanine (Phe). In addition, a Phe-free second stage L-amino acid supplement is usually recommended from around 6 months to replace Phe-free infant formula. Our aim was to assess different weaning approaches used by health professionals across Europe., Methods: A cross sectional questionnaire (survey monkey®) composed of 31 multiple and single choice questions was sent to European colleagues caring for inherited metabolic disorders (IMD). Centres were grouped into geographical regions for analysis., Results: Weaning started at 17-26 weeks in 85% ( n  = 81/95) of centres, >26 weeks in 12% ( n  = 11/95) and < 17 weeks in 3% ( n  = 3/95). Infant's showing an interest in solid foods, and their age, were important determinant factors influencing weaning commencement. 51% ( n  = 48/95) of centres introduced Phe containing foods at 17-26 weeks and 48% ( n  = 46/95) at >26 weeks. First solids were mainly low Phe vegetables (59%, n  = 56/95) and fruit (34%, n  = 32/95).A Phe exchange system to allocate dietary Phe was used by 52% ( n  = 49/95) of centres predominantly from Northern and Southern Europe and 48% (n = 46/95) calculated most Phe containing food sources (all centres in Eastern Europe and the majority from Germany and Austria). Some centres used a combination of both methods.A second stage Phe-free L-amino acid supplement containing a higher protein equivalent was introduced by 41% ( n  = 39/95) of centres at infant age 26-36 weeks (mainly from Germany, Austria, Northern and Eastern Europe) and 37% ( n  = 35/95) at infant age > 1y mainly from Southern Europe. 53% ( n  = 50/95) of centres recommended a second stage Phe-free L-amino acid supplement in a spoonable or semi-solid form., Conclusions: Weaning strategies vary throughout European PKU centres. There is evidence to suggest that different infant weaning strategies may influence longer term adherence to the PKU diet or acceptance of Phe-free L-amino acid supplements; rendering prospective long-term studies important. It is essential to identify an effective weaning strategy that reduces caregiver burden but is associated with acceptable dietary adherence and optimal infant feeding development.

Introduction and Objectives: Metastatic Crohn's disease (MCD) is an extraintestinal manifestation of Crohn's disease, with biopsy as fundamental diagnostic tool. There are few references to MCD in children, with a 0.5-1% estimated incidence in adults. There is no consensus about its therapeutic approach. We describe our diagnostic and therapeutic experience in MCD., Results: Four cases of MCD are described in our Pediatric Gastroenterology Unit in a tertiary care hospital. The age at diagnosis was between 7 and 13 years. Lesions appeared before the diagnosis of Crohn's disease in three of them, and during the course of the disease in another one, with genital location in three patients and bilateral pretibial region in the other. All four cases demonstrated non-caseificant granulomas on biopsy. Only two patients used exclusive enteral nutrition therapy with complete resolution, while other two cases received a combination of therapies (corticosteroids, azathioprine, tacrolimus, infliximab and adalimumab) because of recurrence. Only one case required surgery after poor clinical control., Conclusion: The MCD is infrequent but must always be included in the differential diagnosis of cutaneous lesions in Crohn's disease, considering it could be the debut of the disease. We will rely on biopsy anyway for definitive diagnosis. In this series the genital region is verified as the most commonly affected in children. The therapeutic approach does not differ from the management of intestinal involvement.

Background: Advances in the diagnosis and treatment of urea cycle disorders (UCDs) have led to a higher survival rate. The purpose of this study is to describe the characteristics of patients with urea cycle disorders in Spain., Methods: Observational, cross-sectional and multicenter study. Clinical, biochemical and genetic data were collected from patients with UCDs, treated in the metabolic diseases centers in Spain between February 2012 and February 2013, covering the entire Spanish population. Heterozygous mothers of patients with OTC deficiency were only included if they were on treatment due to being symptomatic or having biochemistry abnormalities., Results: 104 patients from 98 families were included. Ornithine transcarbamylase deficiency was the most frequent condition (64.4%) (61.2% female) followed by type 1 citrullinemia (21.1%) and argininosuccinic aciduria (9.6%). Only 13 patients (12.5%) were diagnosed in a pre-symptomatic state. 63% of the cases presented with type intoxication encephalopathy. The median ammonia level at onset was 298 μmol/L (169-615). The genotype of 75 patients is known, with 18 new mutations having been described. During the data collection period four patients died, three of them in the early days of life. The median current age is 9.96 years (5.29-18), with 25 patients over 18 years of age. Anthropometric data, expressed as median and z-score for the Spanish population is shown. 52.5% of the cases present neurological sequelae, which have been linked to the type of disease, neonatal onset, hepatic failure at diagnosis and ammonia values at diagnosis. 93 patients are following a protein restrictive diet, 0.84 g/kg/day (0.67-1.10), 50 are receiving essential amino acid supplements, 0.25 g/kg/day (0.20-0.45), 58 arginine, 156 mg/kg/day (109-305) and 45 citrulline, 150 mg/kg/day (105-199). 65 patients are being treated with drugs: 4 with sodium benzoate, 50 with sodium phenylbutyrate, 10 with both drugs and 1 with carglumic acid., Conclusions: Studies like this make it possible to analyze the frequency, natural history and clinical practices in the area of rare diseases, with the purpose of knowing the needs of the patients and thus planning their care.

Introduction: The conventional 24-hour pH monitoring is the gold standard for the diagnosis of gastro-esophageal reflux (GER), a possible cause of Apparent Life Threatening Episodes (ALTE). However, multichannel intraluminal impedance (MII) may provide advantages., Objectives: Comparison of the results of MII and pH monitoring in patients undergoing MII-pH monitoring in the 3-year study period because of having suffered from ALTE., Material and Methods: Prospective study of MII-pH monitoring performed in our unit to infants < 12 months of ageadmitted for ALTE for a 3-year period., Results: Thirty nine patients studied. 2,692 pH monitoring episodes, with median of 24 (IQ: 15-44) episodes/patient, 1.30 (IQ: 0.80-2.60) reflux/hour, 1 (IQ: 0-4) reflux episode > 5 min per patient and clearance of 1.20 (IQ: 0.70-2.20) min/reflux. With pH monitoring analysis, 14 children (35.9 %) could have been diagnosed as GER (8 mild, 4 moderate and 2 severe) based on the classical criteria. MII identified a total of 8,895 events; only 3,219 among them were refluxes, with a median of 75 (IQ: 54-111) per patient, 1.30 (IQ: 1.3-2.6) episodes/hour). With MII-pH monitoring combination there were 21.60 (SD 15.21) acid reflux episodes, 67.33 weekly acid (SD 32.09) and 3.34 (SD 7.23) non-acid, being finally diagnosed 33 patients as GER., Conclusions: The association of pH monitoring and MII provides additional information that improves GER diagnostic performance without posing any additional risk to the infant patient. The non-acid/weekly acid refluxes, not detected by pH monitoring, account for a high percentage of episodes, this may have diagnostic and therapeutic significance, especially in infants. Further studies are needed to assess the normality of MMI in pediatric patients.